Autophagy and Inflammasome activation triggered by LPS-negative Ehrlichia is dependent on both mTOR activation and MyD88 signaling

Lipopolysaccharide (LPS) positive pathogens trigger autophagy and inflammasome activation. Autophagy is an innate anti-microbial host defense that maintains tissue homeostasis and is regulated by the nutrient-sensing mTORC1 complex. However it is unknown how the LPS-negative, Gram negative Ehrlichia elicits the same response. Monocytic Ehrlichia triggers Type I IFN-dependent NLRP3 inflammasome activation, which detrimentally effects host response to Ehrlichia . In this study, we examined the regulatory mechanisms of autophagy and inflammasome activation. With toll like receptor (TLR)-adaptor molecule MYD88 deficient mice, we reveal a crucial role for MYD88 in mediation of Ehrlichia- dependent inflammasome activation and hepatic inflammation. This role is demonstrated by decreased Caspase 1 and IL-1β levels in infected liver tissues, and decreased inflammatory cytokines (TNF-α and IL-6) when compared to wild type. Ehrlichia -induced inflammasome activation in wild type mice correlated with inhibition of autophagy . Ehrlichia -induced inhibition of autophagy in infected macrophages was dependent on TLR9, TLR2, and their adaptor MYD88. Inhibition was enhanced by IFN-β stimulation. We also demonstrate that mTORC1 autophagy inhibition acts downstream of MYD88. These data suggest that LPS-negative Ehrlichia inhibit autophagy and activate the inflammasome through mTORC1 activation and MYD88 signaling, contributing to Ehrlichia- induced inflammatory disregulation and liver injury.